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Nature. 2017 Nov 2;551(7678):51-56. doi: 10.1038/nature24281. Epub 2017 Sep 27.

Two independent modes of chromatin organization revealed by cohesin removal.

Author information

1
Developmental Biology Unit. European Molecular Biology Laboratory. 69117 Heidelberg, Germany.
2
Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
3
Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
4
Genome Biology Unit. European Molecular Biology Laboratory. 69117 Heidelberg, Germany.
5
Institute for Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts USA.
6
Institut Pasteur, (Epi)genomics of Animal Development Unit, Developmental and Stem Cell Biology Department. Institut Pasteur. 75015 Paris, France.
7
CNRS, UMR3738, 25 rue du Dr Roux, 75015 Paris, France.
8
European Bioinformatics Institute. European Molecular Biology Laboratory. Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
9
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.

Abstract

Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.

PMID:
29094699
PMCID:
PMC5687303
DOI:
10.1038/nature24281
[Indexed for MEDLINE]
Free PMC Article

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